Abstract PS3-02-23: Hereditary Breast Cancer (BC) in the Moderate-Risk Spectrum - Surgical Practices and Risk of Second Primary Tumors

Abstract Background: Hereditary breast cancer represents 5-10% of all cases. While BRCA1/2 pathogenic variants (VP) are well-established high-risk factors, clinical implications of moderate-penetrance gene VP (PALB2, CHEK2, ATM, RAD51C, RAD51D, BARD1, BRIP1, FANCM) remains less explored. Global prevalence estimates for moderate-penetrance genes such as PALB2, CHEK2 and ATM range between 1-3%, underscoring the clinical relevance of tailored management. Definition of optimal surgical strategies and surveillance, particularly based on the prevalence of second primary tumors, are needed. We aimed to evaluate surgical management strategies and the prevalence of second primary tumors in patients with hereditary breast cancer associated with moderate-penetrance gene mutations, to inform clinical decision-making and surveillance recommendations. Methods: A retrospective cohort study was conducted at A.C. Camargo Cancer Center including women diagnosed with BC and VP in moderate-penetrance genes between 2016-2025. Descriptive statistics summarized clinical-pathological data. Cumulative incidence of second primary tumors and breast cancer (BC) recurrence was calculated. Five-year overall survival (OS) was estimated by the Kaplan-Meier method. Moderate-risk classification was defined according to current NCCN guidelines and a comprehensive hereditary cancer NGS panel. Results: Among 1,429 patients tested, 120 (8%) had VP in moderate-penetrance genes: 28 PALB2, 28 CHEK2, 28 ATM, 15 RAD51C, 4 RAD51D, 6 FANCM, 8 BRIP1, 3 BARD1. They were all female. Family history of BC was present in 73%. Most were diagnosed at stage I (54%). Predominant histology was invasive ductal carcinoma (79%), with SBR grade 3 in 63%. Subtypes included: Luminal B (24%), HER2-low (23%), HER2-overexpressing Luminal B (19%), TNBC (18%), Luminal A (10%) and HER2 -overexpressing (4%). Contralateral synchronous BC occurred in 3 patients (2%). Unilateral adenomastectomy was the most common surgical approach (51%), followed by segmental resection (45%). Four percent of patients underwent bilateral adenomastectomy. Sentinel lymph node biopsy was performed in 67%; axillary dissection in 33%. Over a median follow-up of 5 years, second primary tumors were observed in 16 patients (13.2%): 7 papillary thyroid carcinomas (5 CHEK2, 2 ATM), 6 ovarian cancers (1 ATM, 5 RAD51C), and single cases of melanoma, endometrial, lung, and colorectal cancer. BC recurrence occurred in 8 patients (6.6%). Prophylactic salpingo-oophorectomy was performed in 17%. The 5-year OS was 96.8%. Conclusion: Unilateral mastectomy with sentinel lymph node biopsy was the most frequent surgical strategy for moderate penetrance gene VP carriers. Despite excellent OS, patients with VP in moderate-penetrance genes—especially CHEK2, ATM, and RAD51C —faced a significant cumulative incidence of second primary tumors (13.2%), with thyroid and ovarian cancers being the most prevalent. These findings highlight the need for tailored surveillance strategies beyond breast-focused care in this genetically distinct population. This highlights the need for a multidisciplinary approach involving breast surgeons, genetic counselors, gynecologists, and endocrinologists to optimize long-term surveillance beyond breast-focused care. Breast surgeons should also consider bilateral prophylactic mastectomy in highly selected moderate-risk cases to further reduce long-term risk. Citation Format: A. L. Cicilini, J. C. Casali-da-Rocha, F. B. Makdissi, S. M. Sanches, S. M. Volc, R. Cagnacci-Neto, F. P. Leite, S. M. Castro, M. Sonagli, D. G. Rodrigues de Souza, P. V. de-Cerqueira, V. P. de Souza, L. R. Soares, V. C. Cordeiro de Lima, A. A. Balieiro, S. M. Caputo, E. Santana dos Santos. Hereditary Breast Cancer (BC) in the Moderate-Risk Spectrum - Surgical Practices and Risk of Second Primary Tumors abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-02-23.